PARAOXONASE AND CORONARY HEART-DISEASE

Paraoxonase (PON1) hydrolyses organophosphate insecticides and nerve g ases and is responsible for determining the selective toxicity of thes e compounds in mammals. Human PON1 has two genetic polymorphisms givin g rise to amino-acid substitutions at positions 55 and 192. The 192 po lymorphism is the major determinant of the PON1 activity polymorphism towards organophosphates. However, the 55 polymorphism also modulates activity. Ex vivo, the PON1 polymorphisms are important in determining the capacity of HDL to protect LDL against oxidative modification in vitro and this may explain the relationship between the PON1 alleles a nd coronary heart disease in case-control studies. In recent case-cont rol studies serum PON1 concentration and activity were also found to b e decreased in coronary heart disease (CHD) independent of the PON1 po lymorphism, and in diabetes serum PON1 specific activity decrease is a lso independent of the PON1 genetic polymorphism. HDL from transgenic mice lacking PON1 fails to protect LDL against oxidative modification. Thus PON1 may be a determinant of resistance to the development of at herosclerosis by protecting lipoproteins against oxidative modificatio n, perhaps by hydrolysing phospholipid and cholesteryl-ester hydropero xides. Curr Opin Lipidol 9:319-324. (C) 1998 Lippincott-Raven Publishe rs.